The use of active pharmaceutical ingredients (“APIs” or in the singular form “API”) that have chemical reactivity in water in high dose tablet dosage forms where the API comprises the majority of the pharmaceutical formulation (defined as 75% w/w or more of API in a single tablet) is challenging for pharmaceutical formulation scientists. These high dose tablet dosage forms are challenging because (1) the compaction properties of the API are critical to the formation of a robust tablet dosage form, (2) the small quantity of excipient(s) per tablet makes it difficult to get suitable compression, and (3) the chemical reactivity of certain APIs makes common processing techniques for ordinary high dose tablet dosage forms unacceptable. A person of skill in the art understands that an excipient is an inert ingredient that is acceptable for use in a finished pharmaceutical dosage form.
For high dose tablet dosage forms, it is common to use the wet granulation processing technique to impart suitable compaction properties to the mixture of the active pharmaceutical ingredient(s) and the excipient(s). A person of skill in the art understands that wet granulation creates an intimate mixture of the pharmaceutical formulation ingredients that promote both improved flow and compaction properties thereby modifying the properties of the API to the greatest extent of any of the pharmaceutical processing techniques. Wet granulation often utilizes binder solutions to wet mass the formulation mixture creating, in many cases, API particles with binder on the surface of each secondary particle, so during compaction it is the binder material that makes direct contact with other binder material to form the finished tablet dosage form. These secondary API particles comprised not only of API, but of the formulation mixture, will demonstrate improved compaction properties. As defined above for high dose tablet dosage forms, the formulation mixture of the active pharmaceutical ingredient(s) and the excipient(s) contains a higher percentage of the active pharmaceutical ingredient(s), typically 75% w/w or more, when compared to the percentage of excipient(s); thus, wet granulation is particularly valuable to impart suitable compaction properties and form satisfactory finished tablet dosage forms. For active pharmaceutical ingredient(s) with sensitivity to water, however, typical aqueous-based wet granulation may not be an option because wet granulation will expose the API(s) to water.
Even direct compression, also known to the those in the art as dry blend processing, can present challenges when dealing with APIs that have chemical reactivity in water in high dose tablet dosage forms. Without the ability to modify the compaction properties of the API using wet granulation, the flow and compaction properties of the neat API become critical to the formation a robust tablet dosage form.
In direct compression, the residual moisture content of the final blend (or in the case of a high dose tablet dosage form, the moisture content of the API itself) must be considered and increasing this moisture content is typically used to improve the compaction properties of the final blend. For APIs that are sensitive to water, however, increasing moisture content is not suitable because it can result in degradation of the API. On the other hand, a simple reduction in moisture content of the API to reduce the chemical reactivity or degradation can also be counterproductive to the formation/compaction of the high dose tablet dosage form, which is why formulating a high dose tablet dosage form with an API that is sensitive to water can be a significant challenge to a pharmaceutical formulation scientist.
Methenamine salts (including mandelate and hippurate salt forms) are an example of APIs that have the abovementioned chemical reactivity in water. Methenamine salts act as urinary antibacterial agents that react in acidic aqueous medium to form ammonia and the antibacterial agent, formaldehyde. The therapeutic activity of methenamine salts also requires a high dosage in order to be effective. Commercially available tablets containing methenamine salts are available in 500 mg and 1,000 mg formulations. The mechanism of action of methenamine salts illustrates why the water content in a high dose tablet dosage form of a methenamine salt is critical. For the avoidance of doubt, the methenamine salts react in an aqueous media, so controlling the amount of water in the dosage form protects the methenamine salt from reacting with the residual water. Because the sensitivity to water is only a concern for the methenamine moiety, a formulation of any salt form of methenamine (including mandelate and hippurate) faces the same challenge with respect to water content. For ease of discussion, this specification focuses on methenamine mandelate, but a person of skill in the art understands that the concepts herein apply to any salt form of methenamine.
Following administration as a pharmaceutical tablet dosage form, methenamine mandelate is rapidly absorbed (as methenamine and mandelic acid) and excreted by the kidney to concentrate in the urine. The antibacterial therapeutic activity is primarily the result of hydrolysis of the methenamine moiety, which is maximized at a pH of 5.5 or less in the urine. Mandelic acid also provides antibacterial activity, and it aids in the effectiveness of the methenamine moiety because the mandelic acid acidifies a patient's urine. While the normal range for urine pH is 4.6-8.0 depending on the materials excreted by the kidney, the presence of mandelic acid will lower the pH of a patient's urine, which enhances the effectiveness of the methenamine moiety.
The symbiosis of the methenamine moiety and mandelic acid poses a challenge to the pharmaceutical scientist. Methenamine mandelate, like any other API, has an inherent moisture content as a bulk drug substance. In the micro environment surrounding each API crystal, the moisture/water present in the API is, in fact, a saturated solution of both methenamine and mandelic acid providing an ideal environment for hydrolysis or drug degradation. Controlling the water content of the API thus helps to prevent hydrolysis or drug degradation and this is valid for both the bulk drug substance and in the finished tablet dosage form.
The United States Pharmacopeia (USP) sets limits for moisture content of APIs. The USP monograph for methenamine mandelate establishes a specification of less than 1.5% moisture content using the general physical USP test, Loss on Drying <731>. The USP monograph for methenamine hippurate establishes a specification of less than 1.0% moisture content using the general physical USP test, Loss on Drying <731>. Controlling the water content to a specification lower than the limit specified in the USP results in a finished dosage product with less hydrolysis, which in turn decreases the potential for drug degradation and improves the shelf life of the finished dosage product.